Structural Insights in Mammalian Sialyltransferases and Fucosyltransferases: We Have Come a Long Way,but It Is Still a Long Way Down

Mammalian cell surfaces are modified with complex arrays of glycans that play major roles in health and disease. Abnormal glycosylation is a hallmark of cancer; terminal sialic acid and fucose in particular have high levels in tumor cells, with positive implications for malignancy. Increased sialylation and fucosylation are due to the upregulation of a set of sialyltransferases (STs) and fucosyltransferases (FUTs), which are potential drug targets in cancer. In the past, several advances in glycostructural biology have been made with the determination of crystal structures of several important STs and FUTs in mammals. Additionally, how the independent evolution of STs and FUTs occurred with a limited set of global folds and the diverse modular ability of catalytic domains toward substrates has been elucidated. This review highlights advances in the understanding of the structural architecture, substrate binding interactions, and catalysis of STs and FUTs in mammals. While this general understanding is emerging, use of this information to design inhibitors of STs and FUTs will be helpful in providing further insights into their role in the manifestation of cancer and developing targeted therapeutics in cancer.     

One‐pot PTC synthesis of polyfused pyrazoles

Thienopyrazole 2 , 3 , 5 , or 6 and thienopyrazolothiazepine 7, 9 , and 11 derivatives were prepared via the reaction of the 3‐aminopyrazoline‐5‐one 1 with CS₂ and different molar ratio of a variety of halo compounds having an active methylene under PTC conditions. Also, treatment of 1 with CS₂ and alcoholic KOH in 2:1:1 molar ratio afforded dipyrazolopyridine derivatives 12 and 14 . On other hand, the pyrazolothiadiazineone derivative 13 was obtained by treating compound 1 with CS₂ and alcoholic KOH in 1:2:2 molar ratio. Under PTC conditions, compound 1 , CS₂, and ethyl cyanoacetate or malononitrile to gave the pyrazolopyridine derivatives 16 and 17 . Coupling of compound 1 with diazonium acetates afforded the hydrazone derivatives 18a,b , which were oxidized with bromine to give pyrazolotriazoles 19a,b or cyclized with aldehydes to give pyrazolotriazine derivatives 20a–e . Bromination of compound 1 afforded monobromopyrazole derivative 21 , which could be condensed to a dipyrazolopyrazindione 23 . Finally, the dibromopyrazole derivative 22 was cyclized with 2‐mercaptoethanol or o‐phenylenediamine to give the spiropyrazoles 24a,b . © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:211–217, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10129     

Deciphering the Potential of Pre and Pro-Vitamin D of Mushrooms against Mpro and PLpro Proteases of COVID-19: An In Silico Approach

Vitamin D’s role in combating the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, has been established in unveiling viable inhibitors of COVID-19. The current study investigated the role of pre and pro-vitamin D bioactives from edible mushrooms against Mpro and PLpro proteases of SARS-CoV-2 by computational experiments. The bioactives of mushrooms, specifically ergosterol (provitamin D₂), 7-dehydrocholesterol (provitamin-D₃), 22,23-dihydroergocalciferol (provitamin-D₄), cholecalciferol (vitamin-D₃), and ergocalciferol (vitamin D₂) were screened against Mpro and PLpro. Molecular docking analyses of the generated bioactive protease complexes unravelled the differential docking energies, which ranged from −7.5 kcal/mol to −4.5 kcal/mol. Ergosterol exhibited the lowest binding energy (−7.5 kcal/mol) against Mpro and PLpro (−5.9 kcal/mol). The Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) and MD simulation analyses indicated that the generated complexes were stable, thus affirming the putative binding of the bioactives to viral proteases. Considering the pivotal role of vitamin D bioactives, their direct interactions against SARS-CoV-2 proteases highlight the promising role of bioactives present in mushrooms as potent nutraceuticals against COVID-19.     

Symmetric sums of squares over k-subset hypercubes

Mathematical Programming - We consider the problem of finding sum of squares (sos) expressions to establish the non-negativity of a symmetric polynomial over a discrete hypercube whose coordinates...     

Photolytic metallization of au nanoclusters and electrically conducting micrometer long nanostructures on a DNA scaffold

An electroless, photolytic method is described to synthesize Au nanoclusters and electrically conductive, micronmeter long nanostructures on DNA. Electrical characterization indicates that the Au nanostructures are continuous, exhibiting Ohmic behavior with very low contact resistance with the electrodes. The nanoclusters have a size of 10-40 nm, and the nanostructure have a diameter of 40-70 nm with resistivity comparable to that of pure metal. The method is highly selective with deposition confined to the DNA template.     

Accelerating Branch-and-Bound through a Modeling Language Construct for Relaxation-Specific Constraints

In the tradition of modeling languages for optimization, a single model is passed to a solver for solution. In this paper, we extend BARON’s modeling language in order to facilitate the communication of problem-specific relaxation information from the modeler to the branch-and-bound solver. This effectively results into two models being passed from the modeling language to the solver. Three important application areas are identified and computational experiments are presented. In all cases, nonlinear constraints are provided only to the relaxation constructor in order to strengthen the lower bounding step of the algorithm without complicating the local search process. In the first application area, nonlinear constraints from the reformulation–linearization technique (RLT) are added to strengthen a problem formulation. This approach is illustrated for the pooling problem and computational results show that it results in a scheme that makes global optimization nearly as fast as local optimization for pooling problems from the literature. In the second application area, we communicate with the relaxation constructor the first-order optimality conditions for unconstrained global optimization problems. Computational experiments with polynomial programs demonstrate that this approach leads to a significant reduction of the size of the branch-and-bound search tree. In the third application, problem-specific nonlinear optimality conditions for the satisfiability problem are used to strengthen the lower bounding step and are found to significantly expedite the branch-and-bound algorithm when applied to a nonlinear formulation of this problem.     

Quantum noise measurements in a continuous-wave laser-diode-pumped Nd:YAG saturated amplifier

We present measurements of the power noise due to optical amplification in a Nd:YAG free-space traveling-wave amplifier as the amplifier transitions from the linear regime into the heavily saturated regime. The quantum noise behavior is demonstrated by saturating the gain of a 100-W class zigzag slab amplifier with a high-power beam and measuring the power noise detected by a single-spatial-mode probe beam traversing the same optical path through the amplifier.     

Separation and Characterization of New Forced Degradation Products of Macitentan: A Dual Endothelin Receptor Antagonist

Macitentan (MCT) is an endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension. In the present study, MCT was subjected to forced degradation as per ICH guidelines. The drug degraded extensively in acidic, basic as well as neutral hydrolytic conditions and seven degradation products (DPs) were formed. All these DPs were selectively separated using high-performance liquid chromatography (HPLC) with a stationary phase of Inertsil C₁₈ column (150 × 4.6 mm, 5 μm) and a mobile phase consisting of gradient mixture of 0.02% trifluoroacetic acid (TFA) and acetonitrile (ACN). The developed HPLC method was transferred to LC–ESI–QTOF–MS/MS for identification of DPs. The final mass spectrometric conditions were optimized for better ionization of drug and DPs with optimum mass signal sensitivity. All the formed DPs were new and well separated with sufficient resolution. The developed HPLC method was validated as per ICH-guidelines and can be used in drug testing labs for determination of quality of MCT in bulk and finished formulations.